Integrated Proteomics and Metabolomics Analysis in Hippocampus of Rats With <scp>T2DM</scp> ‐Associated Cognitive Decline

Type 2 diabetes mellitus (T2DM) is currently one of the most prominent and global chronic conditions. Cognitive decline is one of the major complications of T2DM, but its precise molecular mechanism remains unclear. Metabolomics and proteomics were combined in this study to investigate alterations in metabolites and proteins in the hippocampus of T2DM rats. KEGG Markup Language (KGML) network analysis was conducted to integrate underlying relationships among differentially expressed metabolites and proteins. 58 significantly differentially expressed metabolites and 61 differentially expressed proteins were identified between T2DM and CON rats. In proteomic analysis, GO analysis showed that DEPs involved in biological process were mainly related to neurofilament cytoskeleton organization, postsynaptic actin cytoskeleton organization and actin filament severing. KEGG pathway analysis showed the major enriched pathways were thiamine metabolism, cholesterol metabolism, pentose phosphate pathway (PPP), ABC transporters and regulation of actin cytoskeleton. In metabolomics analysis, KEGG pathway analysis showed the major enriched pathways were autophagy, lysosome, glycolysis/gluconeogenesis, PPP and ABC transporters. KGML network analysis revealed that PPP and ABC transporters were activated in the hippocampus of T2DM rats, accompanied by the up-regulation of metabolites in two pathways. Rpia was up-regulated, which is the indicator of increased PPP flux. Tap1, the unique immune-function ABC transporter, was up-regulated. Excessive PPP activation disrupts cognition-related synaptic transmission, while up-regulated immune-function ABC transporters drive aberrant synaptic remodeling and chronic neuroinflammation. These results provide a better understanding of biological mechanisms underlying T2DM-related cognitive dysfunction and may help identify potential targets for neuroprotective drugs against cognitive dysfunction in T2DM.